Work-life balance: Brain stem cells need their rest, too

LA JOLLA, CA—Stem cells in the brain remain dormant until
called upon to divide and make more neurons. However, little has
been known about the molecular guards that keep them quiet. Now
scientists from the Salk Institute for Biological Studies have
identified the signal that prevents stem cells from proliferating,
protecting the brain against too much cell division and ensuring a
pool of neural stem cells that lasts a lifetime.

The research, which will be published in the July 1 issue of
Cell Stem Cell, highlights the importance of bone morphogenetic
factor protein (BMP) signaling for the maintenance of a neural stem
cell reservoir throughout adult life and may provide the key to
understanding the interplay between exercise, aging and
neurogenesis.

Adult neural stem cells in the hippocampus—a memory hub of
the brain—sprout new brain cells throughout life. This
particular area of the brain, one of only two for which
neurogenesis has been clearly shown, is particularly vulnerable to
age-related degeneration. Regular physical exercise not only slows
the shrinking of aging hippocampi but also improves learning and
memory in mature adults.

"This study provided us with very important insights into how
adult stem cells are regulated, says senior author Fred H. Gage,
Ph.D., a professor in the Laboratory for Genetics at the Salk
Institute and the Vi and John Adler Chair for Research on
Age-Related Neurodegenerative Diseases. "Going forward, we can
start to tinker with this mechanism to understand how exercise
influences the aging brain."

During the process of neurogenesis, neurons-to-be pass through
several distinct stages, including cell birth, fate determination,
survival, integration, and acquisition of functional
properties.

"Each stage is driven by a complex interplay between intrinsic
mechanisms and environmental cues," says co-first author Helena
Mira, formerly a post-doc in the Gage laboratory and now an
assistant professor in the Department of Cell Biology and
Development at the Carlos III Health Institute?in Madrid. "We
already knew a lot about fate choice and differentiation, but it
was unclear how neural stem cells decided to divide or not in the
first place."

Using their observation that quiescent neural stem cells express
the BMP receptor 1A as a starting point, Mira and her collaborators
investigated the role of BMP signaling in regulating the
proliferation of stem cells located in the hippocampus, one of two
brain regions harboring neural stem cells.

They found that BMP signaling, which is triggered by the
interaction of BMPs with their receptors, is inactive in most
proliferating cells, whereas it is active in non-dividing cells,
including quiescent stem cells and differentiated neurons. Unlike
stem cells, mature neurons express BMP receptor 1B, which will be
the focus of future studies.

Experiments with cultured neural stem cells confirmed that it
was indeed BMP that kept them quiet. BMP's anti-proliferative
effect was blocked when BMP was replaced with a protein known as
Noggin, which binds and inactivates members of the BMP family.

The researchers observed the same effect when they delivered
Noggin directly into the brains of adult mice. Here, too, Noggin
successfully interfered with BMP signaling and raised quiescent
stem cells out of their slumber. After one week, those neural stem
cells had started dividing and their offspring were well on their
way to becoming neurons.

When neural stem cells were forced to proliferate over prolonged
periods of time, however, the pool of active neural stem cells was
depleted, suggesting to Gage and his team that quiescence functions
as a protective mechanism that counteracts stem cell exhaustion and
bursts of dividing cells, which could lead to tumors.

"It tells you how finely this process is regulated," says Mira.
"BMP ensures a sufficiently big population of quiescent stem cells
that can feed into the system when called upon."

BMP may also be the linchpin that links exercise, aging and
neurogenesis. "As we age, the number of new neurons declines but
physical exercise brings that number back up," says Gage. "Our
findings raise the possibility that the BMP signal becomes dominant
over time, forcing neural stem cells deeper into quiescence and
thus making it harder to generate new brain cells."

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Researchers who also contributed to the study include Zoraida
Andreu, Juana San Emeterio, and Rafael Hortigüela at the
Carlos III Health Institute, Madrid, Hoonkyo Suh, Antonella
Consiglio and Kinichi Nakashima at the Salk Institute for
Biological Studies, La Jolla, María Ángeles
Marqués-Torrejón and Isabel Fariñas at the
University of Valencia, Spain, D. Chichung Li, Dilek Colak and
Magdalena Götz at the Helmholtz Center Munich, Germany, as
well as Sebastian Jessberger at the ETH Zurich, Switzerland.

The work was in part funded by the Deutsche
Forschungsgemeinschaft, the Programa Ramon y Cajal from the Spanish
Ministerio de Educacion y Ciencia, the Centro de
Investigación Príncipe Felipe, and the Helmholtz
Association.

About the Salk Institute for Biological Studies?

The Salk Institute for Biological Studies is one of the world's
preeminent basic research institutions, where internationally
renowned faculty probe fundamental life science questions in a
unique, collaborative, and creative environment. Focused both on
discovery and on mentoring future generations of researchers, Salk
scientists make groundbreaking contributions to our understanding
of cancer, aging, Alzheimer's, diabetes, and infectious diseases by
studying neuroscience, genetics, cell and plant biology, and
related disciplines. Faculty achievements have been recognized with
numerous honors, including Nobel Prizes and memberships in the
National Academy of Sciences. Founded in 1960 by polio vaccine
pioneer Jonas Salk, M.D., the Institute is an independent nonprofit
organization and architectural landmark.

The Salk Institute proudly celebrates five decades of scientific
excellence in basic research.